All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Preterm birth (less than 37 completed weeks of gestation) is one of the major problems and challenges in obstetrics. The frequency of preterm births is about 12-13% in the USA and 5-9% in many other developed countries.1,2 Despite all efforts to reduce the number of preterm births the problem is continuing to escalate. Since 1990 the percentage of births delivered preterm has risen more than 20 percent and is 36 percent higher since the early 1980s in the USA.3 Preterm birth is not only a major determinant of neonatal and infant morbidity, including neurodevelopmental handicaps, chronic respiratory problems, intraventricular hemorrhage, infection, retrolental fibroplasia, and necrotizing enterocolitis, but it is also the single most important cause of perinatal mortality in North America, Europe and particularly in undeveloped countries.4 Additionally, the neonatal and long-term health care costs of preterm infants impose a considerable economic strain both on individual families and on healthcare costs (>$26.2 billion in 2005 in the USA).5,53 There is a need in the art for novel and effective treatments for preterm delivery.
Both uterine and cervical functions play important roles in the onset and progression of term and preterm labor and delivery. Ripening of the cervix is an inflammatory-like reaction with infiltration of leukocytes, increase of cytokines (interleukin (IL)-1 and IL-8) and an increase in metalloproteinases (MMPs), with MMPs playing a key role in ECM remodeling.8,9,10 Following cervical ripening, uterine contraction and cervical dilation results in delivery of the fetus. Uterine contraction results from the biomechanical coupling of actin and myosin, which depends on the phosphorylation of myosin by myosin light-chain kinase (MLCK). The activation of MLCK by various uterotonins, including oxytocin and prostaglandins, fosters actin-myosin coupling, leading to synchronous high-amplitude activity in cell-cell connections that generate contractions in the uterus.
Both processes of cervical ripening and uterine contractility are regulated by steroid hormones (in particular progesterone (P4) and estrogen) and progesterone has been known to be used for recurrent or high risk preterm labor (PTL).17-26,32 However, P4 used to treat preterm labor and uterine contractile disorders is often delivered through inconvenient and less effective routes of vaginal, oral or intramuscular delivery. Further, P4 exhibits some measure of non-specificity for non-progesterone receptors, leading to potentially undesirable side effects.
Trimegestone (TMG), a 19-norpregnane derivative progestin, has been used in clinical trials as a proposed treatment for hormone replacement therapy, as well as for oral contraception.57-62 To date, the efficacy of compounds such as TMG has not been shown in treatments for pre-term pregnancy. As a “next generation” progestin (i.e., synthetic or exogenous progestogen), TMG exhibits a 6-fold higher affinity for progesterone receptor (PR) than P4, with much greater potency.11,12 This activity is coupled with higher selectivity for the PR compared to other steroid hormone receptors. For example, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor.12,14,64,65 These pharmacological differences may result in notably different biological effects. For example, TMG also exhibits a differential effect on MMP expression in cultured stromal cells when compared to P4 administration.13 TMG also exhibits antiestrogenic activity in processes related to rat uterine decidualization and ovulation assays, and possesses the highest level of estrogenic activity antagonism in the uterine endometrium among reference progestins.67 Together, these results suggest TMG may be a potent compound for inhibiting cervical ripening and uterine contractility, with further opportunities to apply TMG in new therapeutic avenues, such as dysmenorrhea.68 
These features of TMG present intriguing questions of how TMG application for preterm pregnancy treatment compares to P4 administration, and if higher PR specificity coupled with different mechanisms of action may lead to improved methods of treatment and/or administration.11 